Abstract
Limb–body wall complex (LBWC) refers to a combination of multiple malformations involving the craniofacial structures, thoracoabdominal wall, extremities, and spine. The classic clinical triad of LBWC includes a craniofacial defect (characteristically exencephaly or encephalocele with facial cleft), limb deformity, and body wall malformation with evisceration. The associated anomalies also often involve extensive lesions of the thoracoabdominal region with visceral herniation, a short or absent umbilical cord, and exteriorization of the fetal heart and bladder. Theories regarding the etiology of LBWC include early amnion rupture causing mechanical injury, defective development in the germinal disk, and vascular disruption during embryogenesis. The main features of LBWC can be identified by routine obstetric ultrasound (US); however, diagnosis during the second trimester can be challenging because of associated oligohydramnios. Magnetic resonance imaging has been reported to be a useful adjunct to US in the diagnosis because it provides more comprehensive images of congenital anomalies. There are currently no prenatal or postnatal treatment options for fetuses with LBWC; termination of pregnancy should be offered because this abnormality is uniformly lethal.
Keywords
limb–body wall complex, body wall defect, exencephaly, encephalocele, abdominoschisis, thoracoabdominoschisis, ectoderm
Introduction
Limb–body wall complex (LBWC) refers to a combination of multiple malformations involving the craniofacial structures, thoracoabdominal wall, extremities, and spine. LBWC is almost uniformly lethal and associated with a very poor outcome because of, among other factors, pulmonary hypoplasia. The associated anomalies can be significantly disfiguring, often involving extensive lesions of the thoracoabdominal region with visceral herniation, a short or absent umbilical cord, and exteriorization of the fetal heart and bladder. Although what is described as LBWC in the literature includes a highly variable phenotype, clues suggestive of the diagnosis include an asymmetric and/or anteriorly placed cranioschisis (especially if associated with facial cleft); an extensive abdominal wall defect not typical of an omphalocele or gastroschisis; or any concurrence of cranioschisis, limb defect, or thoracoabdominoschisis.
Disorder
Definition
The characteristic defects seen in affected fetuses with LBWC are exencephaly or encephalocele with facial cleft, lateral body wall defect with evisceration, and limb defects.
Prevalence and Epidemiology
LBWC is a rare, sporadic disorder, with an incidence ranging from approximately 0.2 : 10,000 to 1.3 : 10,000 pregnancies.
Etiology, Pathophysiology, and Embryology
In early gestation, the developing embryo changes from a flat, three-layered disk into a cylindric structure through circumferential folding. This process results in closing of the embryonic body, formation of the body stalk, and separation of the intraembryonic coelom (peritoneal cavity) from the extraembryonic coelom (chorionic cavity). Completion of this process forms the umbilical cord. Any disturbance during this folding stage can disrupt the separation process that creates the internal environment of the embryo, distinct from the chorionic cavity.
The pattern of malformations associated with LBWC varies according to the degree of aberrant development of the cephalic, caudal, and lateral folds in early gestation. Defects in the cephalic fold can result in anterior diaphragmatic hernia, ectopia cordis, sternal cleft, and cardiac defects. Incomplete lateral fold closure can produce an omphalocele or massive evisceration of intraabdominal organs, depending on the extent of the abdominal wall defect. Caudal fold defects can lead to cloacal exstrophy, imperforate anus, and intestinal atresia or agenesis.
Various mechanisms have been proposed to explain the pathogenesis of LBWC. The three main theories are (1) early amnion rupture causing mechanical injury, (2) vascular disruption during embryogenesis, and (3) defective development in the germinal disk. Early amnion rupture, which was at one time the most widely accepted theory, accounts for the craniofacial and limb deformities seen in LBWC. According to this theory, the neural tube defects and facial clefts were considered to be a direct consequence of secondary disruption by bands and/or compression, whereas the ventral wall defect was considered a primary malformation. Limb defects were considered to be caused by an amniotic band interfering with limb budding. The theory was supported by case reports documenting the presence of amniotic bands adjacent to major congenital defects. However, this theory does not adequately explain cases showing an intact amniotic membrane or the high prevalence of internal structural defects noted in cases of LBWC. There is also a lack of evidence to support the resorption of amniotic fluid by the chorion, or that the nature of the chorionic surface is such that it would abrade fetal skin. It is also unclear how rupture of the amnion closer to the stages of neural tube and facial closure would have time to develop bands of adequate consequence to become tangled, or otherwise interfere with the planes of closure. Streeter and Hartwig et al., among others, have demonstrated cases of LBWC in the absence of amniotic bands, and with an intact amnion at delivery.
Van Allen et al. proposed a vascular etiology for LBWC and postulated that a disruption of embryonal vessels during the fourth through sixth weeks of gestation led to a systemic impairment of blood flow. This in turn led to tissue ischemia and necrosis, resulting in the associated internal anomalies such as renal and gallbladder agenesis. The cranial anomalies were thought to be a secondary disruption that occurred shortly after closure. The primary concern with this theory is that the ventral wall anomaly and cranial malformations are thought to occur very early in development, at a time when limb buds are early in their appearance; some limb anomalies seen in LBWC, such as terminal limb syndactyly and constriction rings, would appear to relate to an inciting event significantly later in gestation.
Another theory proposed by Hunter et al. suggests that an ectodermal defect of the embryonic disk during embryogenesis leads to the malformations seen in LBWC. The findings of exencephaly/encephalocele are thought to be secondary to a deficient response and growth of ectodermal cells that typically form the forebrain. A deficiency in ectodermal growth can result in the ectodermal-amnion border coming into contact with the malformed forebrain and would explain the frequent attachment of the cranial defect to the amnion, in addition to the often-distorted brain tissue. The same ectodermal deficiency could lead to an associated neural crest deficiency affecting the frontonasal process, leading to facial clefts. An early step in the formation of the lateral abdominal wall is the ventral folding of the lateral margin of the embryonic disk, which is preceded by an increase in ectodermal cell division. An initial ectodermal cell deficiency could result in a delay or disruption of initial folding, resulting in the abdominoschisis and thoracoabdominoschisis anomalies seen in LBWC. The limb anomalies and internal malformations are thought to be the result of secondary vascular compromise.
More recently, evidence has emerged to support the notion of a genetic etiology to LBWC. Using whole exome sequencing, Kruszka et al. were able to identify a de novo heterozygous mutation in the gene IQCK : c.667C>G; p.Q223E in a patient with the phenotypic characteristics of LBWC, which was then confirmed by Sanger sequencing. The p.Q223E mutation affects glutamine, a very conserved amino acid of the IQ domain. In functional studies using morpholino knockdown, the authors were able to reproduce abnormal phenotypes in zebrafish using p.Q223E human IQCK messenger RNA. More cases are needed to confirm IQCK as a causative gene in LBWC, and further investigation involving whole exome sequencing is likely to reveal the involvement of more genes that may or may not be involved in the same cellular pathway.
Manifestations of Disease
Clinical Presentation
The classic clinical triad of LBWC includes a craniofacial defect, limb deformity, and body wall malformation. Some authors have proposed that at least two of the aforementioned defects must be present to meet criteria for LBWC. LBWC shares similarities with amniotic band sequence, where defects are variable, and no two affected cases have the same phenotype.
Several authors have attempted to classify these cases based on the phenotype and the specific fetoplacental relationship. Two distinct phenotypic categories have resulted: (1) cranioplacental and (2) abdominoplacental. The cranioplacental phenotype usually includes cases with craniofacial defects, with facial clefts and upper limb defects, in the presence of amniotic bands. This phenotype favors the more typical amniotic band sequence with broad amniotic adhesions producing disruptive lesions. The placenta may be abnormally attached to the malformed cranial structures. Thoracic, abdominal, and cloacal disruptions are not features of the cranioplacental type of LBWC.
In contrast, fetuses with the abdominoplacental phenotype have body wall defects, with varying degrees of thoracoabdominal evisceration, urogenital anomalies, imperforate anus, meningocele, and severe spinal deformities, with tight attachment of the fetus to the placenta. There is also persistence of the extraembryonic coelom-associated short umbilical cord. Craniofacial defects and amniotic bands are not described in this group. This subset of LBWC can be more clearly explained by a disturbance during the embryonic folding process in early gestation ( Figs. 105.1 and 105.2 ).
